Chronic hepatitis C virus (HCV) infection is a worldwide public health problem with a global prevalence of 2%. A high proportion of those infected are at risk of developing cirrhosis and hepatocellular carcinoma and modeling data predicts that the burden of disease could soon increase substantially. The liver disease associated with chronic infection has led investigators to look for correlates between viral properties and disease progression, severity of disease and the response to antiviral therapy. HCV has been classified into six genotypes but genotype does not appear to influence disease presentation or severity of disease. However, genotype has been identified as a major predictor of response to interferon-based antiviral therapy. Antiviral regimens have been optimized for infections with HCV genotypes 1-4, although treatment strategies for genotypes 5 and 6 have yet to be developed. The molecular basis for the differences in response of HCV genotypes has yet to be determined.